Method of preparing a diazine derivative



Patented July 9, 1946 UNITED STATES, PAT

ENT 'iOF-FICE METHOD OFIPREPARING DIAzIN-E DERIVATIVE Gaetano F. DfAlelio and Ja es:wpfiiierwota;

Pittsfield, Mass, 'as'signors "Giiial Electric Company, a corporatior'iof New York No Drawing. Application September I, 1942, 7 Serial No. 456,929 c This invention relates to the preparation of diazine derivatives-Which: areembraced by the following general formula:

1 Claim. (01. 260 451) one o r more of their hydrogen atoms substituted by, for example, a halogen, more particularly chlorine, bromine, fluorine or iodine. Specific- V :ITL-GNIHRM examples of halogeno-substituted hydrocarbon radicals that R in. the above formula may represent are: chloromethyl, chloroethyl, chlorophenyl, dichlorophenyl, ethyl chlorophenyl, ch10- rocyclohexyl, phenylchloroethyl, bromoethyl, I

bromopropyl, fiuoropheny l, iodophenyl, bromotoly'l,etc. Preferab-ly'R 'is hydrogen. However, there also may be produced in accordance with the present invention compounds such, for in- Illustrative examples of radicals that R in Formula I may represent are: aliphatic (e. g;, methyl, ethyl, propyl, isopropyl, butyl; 'secondarybut'yl, isobutyl, butenyl, amyl, isoamyl, 'hexyl', etc.),"'iri-- eluding cycloaliphatic (e; g., cyclopentyl, cyclo pentenyl, cyclohexyl; cyclohexenyl, cycloheptyl, etc.) aryl (e. g.,'phenyl, diphenyl or Xenyl, naphthyl, etc.); aliphatic-substituted aryl (e. g., toly1, xylyl, ethylphenyl, propylphenyl, isopropylphenyl, allylphenyl, Z-butenylphenyl, tertiary-butylphenyl, etc.) aryl-substituted aliphatic (e. g., benzyl, cinnamyl, phenylethyl, phenylpropyl, etc.) and. their homologueai as well as those groups with I 5 and IV) have the same meanings as Where n (Formula II), R and Z (Formulas II, III v given above with reference to Formula I. c h

The compounds embraced by Formula I maybe used, for example, as pharmaceuticals; plasticizers,fungicides, bactericides, insecticides, a s additives to petroleum products, as an intermediate in the preparation of dyes, drugs, textile assistants and other chemical compounds, for instanc'eas an intermediateinproducing derivatives thereof such asureido, hydrazine, carbainyl, amidine,=inethylol, methylene, etcl, derivatives of --the individual compound represented byrtrmina I. These compounds are especially valuable in the preparation of synthetic resinous compositions. Thus, they may be condensed with, for example, aldehydes, including polymeric aldehydes, hydroxyaldehydes and aldehyde-addition products to yield condensation products having particular utility in the plastics and coating arts. Such condensation products are more fully described and are specifically claimed in our copending application Serial No. 461,770,1iled October 12, 1942, and assigned to the same assignee as the present invention. These compounds also may be compounded with rubber, both natural and synthetic, to modify the propertiesfof the rubber.

For instance, they may be used to accelerate or otherwise facilitate the vulcanization of natural and synthetic rubbers. Instead of using the com pounds in the form shown in Formula l, they may be used in the form of their salts in such applications as above mentioned by way of illustration.

Various methods may be employed to produce the chemical compounds embraced by Formula I. We prefer to prepare them by effecting reaction, in the presence of a hydrohalide acceptor,

between (1) a mercaptodiamino [(NHR)2] 2-mercapto 4,6-di-cyc1opentylamino) 5-ethyl pyrimidine 2-mercapto 4,6-dianilino pyrimidine Z-mercapto 4,6-ditoluido 5-iodophenyl pyrimidine 2-mercapto 4,6-dixy1idino pyrimidine 2-mercapto 4,6-di-(phenethylamino) 5-butyl pyrimidine 2-mercapto 4,6-di-(ethy1phenylamino) 5-tolyl py m in 4-mercapto 2,6-di-(methylamino) 5-methy1 pyrimidine v 2-mercapto ,.4,6-di (chloroethylamino) pyrimi- Maine 7 2-mercapto 4,6di-(bromoxy1idino) 5-chloroethyl pyrimidine 2-mercapto, 4,6-diamino 5-bromotoly1 pyrimidine 2-mercapto 4,6-di-(iodoani1ino) pyrimidine pyrimidine corresponding to the general formula A g Where R has the same meaning as given above with reference to Formula I and (2) a di-(haloalkyl) ether corresponding to the general formula VI XCnR27l' Z-C7LR21LX Where X represents a halogen atom and n, Z and R have the same meanings as given above with reference to Formula I, the reactants being employed in the ratio of at least two mols oi the mercapto diamino pyrimidine of (1) per mol of the di-(haloalkyl) ether or (2). It will be noted that when R in- Formula VI represents hydrogen, the compound may be represented by the formula Illustrative examples of mercapto diamino [(-NHR)2] diazines that may be employed, depending upon the 'desired end-product, are: 1 n

2-mercapto, 4,6 diamino pyrimidine 4-mercapto 2,6-diamino pyrimidine (G-mercapto ZA-diamino pyrimidine) 2-mercapto 4,6-diamino 5-methyl pyrimidine l-mercapto 2,6-diamino 5-ethy1 pyrimidine Z-mercapto 4,6-diamino 5-pheny1 pyrimidine Z-mercapto -bromotoluido G-benzylamino py-.

rimidine 2-toluido l-mercapto 6-methylamino pyrimidine 2-mercapto l-phenylchloroethylamino 6-phenethylamino pyrimidin Z-mercapto e-chloroanilino G-phenethylamino pyrimidine 2-mercapto 4-cycloheptylamino fi-isopropylamino pyrimidine I 2-mercapto 4,6-di-(methylamino) p rimidine Z-mercapto 4,6-di-(ethylamino) 5-fluorophenyl pyrimidine Z-mercapto 4,6-di-(fiuoroanilino) pyrimidine 2-mercapto 4-methylamino 6-amino pyrimidine 2-mercapto l-propenylamino G-amino pyrimidine Z-mercapto 4,6-di-(benzylamino) 5- methyl pyrimidine Illustrative examples of di-(haloalkyl) ethers that may be used, depending upon the particular end-product desired, are:

Di- (chloromethyl) ether Di-(bromomethyl) ether Dialpha-chloroethyl) ether Di-(alpha-bro-moethyl) ether Di-(beta-chloroethyl) ether Di- (beta-br0moethyl) ether Di-(beta-iodoethyl) ether Di-(alpha-chloroethyl) thioether Di-(alpha-bromoethyl) thioether Di- (beta-chloroethyl) thioether Di-(beta-bromoethyl) thioether Chloromethyl beta-chloroethyl ether Bromomethyl beta-bromoethyl thioether Di-(betachloropropyl) ether Di-(beta-bromopropyl) ether Di-(beta-chloropropyl) thioether Di-(beta-bromopropyl) thioether Di-(alpha-phenyl beta-bromomethyl) thioether Di-(a'lpha-phenyl beta-chloroethyl) ether Chloromethyl beta-chlorobutyl ether Chloromethyl beta-chlorobutyl thioether Di-(alpha-chlorobuten-3-Yl) ether Di- (alpha-bromobuten-3-yl) thioether Various 1 hydrohalide' acceptors may be employed. We prefer to use a hydrohalide acceptor that will react with the mercapto pyrimidine to Examples of such acform a water-soluble salt.

amine, triethyl amine, tributyl amine, pyridine, dimethyl aniline, quinoline, etc; quaternaryammonium bases, e. g., tetrameth-yl ammonium'hy .i

droxide, etc.; and the like.

The reaction between, the mercapto diamino pyrimidine and the chosen di- (haloalky-l') "ether may be carried out in any suitable manner,-but preferably is effected in a suitable olvent or mixture of solvents, e. g., water, alcohol, ether, benzene, dioxane, etc. Although. various solvents and solvent mixtures may be employed, forlec'onomic reasons and because of their eminent suitability-we prefer to use water or a mixture of water and alcohol; The reaction' maybe-carried out undera variety of temperatureiandpres-q sure conditions, for instan'ce at' normal, sub-nor-' mal or at elevated temperatures and at'atmos'e-I ph'eric, sub-atmospheric, ,oru super atmospheric pressures. When th'e-..reaction isicarried out .in an aqueous solution it. is usually preferablefto employ an alkali-metalhydroxide as the hydrohalide acceptor. When a' non-aqueous solution constitutes the liquid medium in which the reaction is effected, th'en it isusually desirableto employ a tertiary amine, e. g.,-pyridine', as them"- drohalide acceptor. g

The above reaction maybe represented by the following general equationt' 1 Inthe above equation}; re,presents1a halogen.- atom, and n, R and Z:have the same meanings a g 1 given above with reference to Formula I5;

In order that those skilleddn -the artxbetter. may understand how the present invention may be carried into effect;thefollowing examplesare given by way of illustration. and not by way of. limitation. All parts are by;weig-ht-.

Example 1 55 This example illustrates the preparation .of beta,beta' bis (4,6-diamino -pyrimidyl'-2 thio) diethyl ether, which also may be named bis- [beta 02,6 diamino pyrimidyl-Z thio) ethyl] ether.

Approx.

Parts mol ratio 2-mercapto 4,6-diamino pyrimidine Sodium hydroxide in mixture of 500 parts water and 500 parts alcohol Di-(beta-chloroethyl) ether temperature of the mass for 7 hours. After 0001-: 7

ing', the dprecipitated product comprising diethyl ether was filtered off, washed well with water to remove solublesalts and dried.- A yield of 158parts'of the purified and dried material was obtained. No attempt was made to recover any more product from the mother liquor.

, Example 2 [beta (2,6 diamino pyrimidyl-4 thio) ethyll ether, is' prepared in essentially the same manner as described under Example '1 with the exception that 142 parts of -mercapto 2,6-diaminopyrimi dine are used in place of 142 parts of 2-mercapto ethyl) thioether are used in place of '7la5partsof di-"(beta-chloroethyl) ether.

Examjole 4 Beta,beta -bis-(4,6-diamino pyrimidyl-Z thio) ethyl isopropyl ether, which also may be named beta-(4,6-diamino pyrimidyl-Z thio) ethyl, beta- (4,6-diamino pyrimidyl-Z thio) isopropyl ether, is prepared in essentially the same manner as described under Example 1 withthe exception that 78.5 parts of beta-chloroethyl beta-chloroisopropyl ether are used instead of 71.5 parts of di- (beta c'hloroethyl) ether. 7

Example 5' Beta,beta-bis-[4,6-di (methylamino) pyrimidyl-2' thio] diethyl ether is prepared in essentially thesame manner as described under Example 1 with the exception that parts of 2- mercapto 4,6-di-(methylamino) pyrimidine are used in place of 142 parts of 2-mercapto 4,6-diamino pyrimidine.

' Example 6 1Beta,beta'-.bis-(4,6-diamino pyrimidyl-Z thio) dipropyl ether, which also may be named .bis- [beta-(4,6-diamino pyrimidyl-Z thio) propyll ether, is prepared in essentially the same manner as described under Example 1 with the exception that 85.5 parts of di-(beta-chloropropyl) ether are used invplace of 71.5 parts of di-(beta-chlomethyl) ether. Similarly bis [beta-(4,6 diamino pyrimidyl-Z thio) isopropyl] ether is prepared by using 85.5 parts of di-(beta-chloroiso propyl) ether instead of 715 parts of di-(betachloroethyl) ether as in Example 1.

Example 7 Beta,beta-bis- (2,6-diaminopyrimidyl 4 thio) dipropyl ether and vbeta,beta'-:bis-(2,6-diamino pyrimidyl-4 thio) di-isopropyl ether are prepared I Beta,beta'-bis-(2,6-diamino pyrimidyl-4 thio): diethyl ether, which also may be named hisin essentially the same manner as described under Example 1 with the exception that 85.5 parts of 'di-(beta-chloropropyl) ether or ofdi-(betachloroisopropyl) ether are used instead ofl71.5 parts of di- (beta-chloroethyl) ether and 142 parts of i-mercapto 2,6-diamino pyrimidine are used in place of 142 parts of 2-mercapto 4,6-diamino pyrimidine. v v

Illustrative examples of other compounds em braced by Formula I that may be produced in accordance with the present invention are listed below:

pyrimidyI-Z Beta,-beta'-bis-(4,6-dianilino pyri-midyl-Z thio) diethyl thioether Beta,beta' -bis- [4,6-di- (methylamino) pyrimidyl- 2 thio] diethyl thioether Beta,beta'-bis-(4,6-ditoluido pyrimidyl-Q thio) diethy1 ether 7 c Beta,beta'-bis-(4,6-dixylidino pyrimidyl-2 thio) diethyl ether Beta,beta'-bis'-(4,6-ditoluido pyrimidyl-2 thio) diethyl thioether Beta,beta-bis-(4,6-diamino -methy1 pyrimidyl- 2 thio) diethyl ether v Beta,beta'-bis-(2,6-diamino 5-ethyl pyrimidyl-4 thio) diethyl thioether Beta,beta'-bis- [4,6-di- (phenethylamino) pyrimidyl-2 thio] diethyl ether Beta;beta -bis- 4,6-di- (ethylanilino) pyrimidyl-Z thio] diethyl ether Beta,beta-bis-(4,6-diamino 5-pheny1 pyrimidyl-Z thio) diethyl ether Beta,beta'-bis- [4,6-di-(methy1amino) 5-ethy1 py-.

rimidy1-2 thio] diethyl ether Bis-(4,6-diamino pyrimidyl-Z thio) ether Bis -(2,6-diamino pyrimidyl-4 thio) dimethyl ether Bis- (4,6-diamino pyr'imidyl-Z thio) dimethyl thioether Bis-(2,6-diamino pyrimidyl-4 thio) dimethyl ether dimethyl Bis-(4,6-diamino 5-methy1 pyrimidyl-Z thio) di-f methyl ether Bis-(2,6-diamino 5-phenyl pyrimidylthio) d imethyl thioether Bis-[4,6-di-(methy1amino) pyrimidy1-2 thiol dimethyl ether Bis-(4,6-dianilino pyrimidyl-Z thio) dimethyl ether Bis-(4-methylamin0 G-anilino pyrimidyl-Z dimethyl ether r Alpha,beta'--bis-(4,6-diamino pyrimidyl-Z thio) methyl ethyl ether 1 "thio) Alpha, alpha'-bi's-(4,6-diamino pyrimidyl-2 thio) diethyl ether Alpha, a1pha'-bis- (2,6-diamino pyrimidyl-4 thio) diethyl ether a Alpha,alpha'-bis-[4,(idi (bromotoluido) pyrimidyl-2 thiol dipropyl ether Alpha,beta'-bis-(4,6-diamino 5-iodomethyl pyrimidyl-2 thio) diethyl ether Alpha,:beta' -bis- (4-methylamino 6 chloroethylamino pyrimidyl-2 thio) beta-phenyl alphaethyldibutyl thioether' Beta, beta-bis- [4,6-di-'(cyclohexenylamino) rimidyl 2 thio] diethyl ether Beta,betat-bis-[4,6-di-(al1y1amino) rimidyl-2 thio] dipropylthioether Beta,betaf -bis [2,6-di- (naphthylamino) pyrimidyl-thio] diethyl-thioether Beta,beta'-bis-[4,6 di (octylamino) 5-chl0rophenyl pyrimidy1-2 thio] diethyl ether Beta,beta'-bis-[4,6 di -(chloroanilin'o) 5 butyl pyrimidyl-2 thio] diethyl thioether Beta,beta'-bis- [2,6-.di- (iodotoluido) E-iodophenyl pyrimidyl-4 thiol dipropyl ether Beta,beta'-bis-[4,6 di icyclohexylamino) 5-cyclohexyl pyrimidyl-2 thiol diethyl ether In a manner similar to that described 'above with particular reference to the preparation of :bis-(LB- diazinyl thio), that is, bis-(pyrimidyl thio), dialkyl ethers and thioethers, corresponding derivatives of the 1,2- or vortho-diazines (pyridazines) and of the 1,4- or para-diazines (pyrazines) may be prepared.

What we claim asnew and desire to secure by Letters Patent of the United .States is:

The method 'of preparing beta,beta'-bis- (4,6- diamino pyrimidy1-2 thio) diethyl ether which comprises addingdi-(beta-chloroethyl) ether to 5 xenyl .a clear solution obtained by mixing together approximately equal molar ratios of 2-mercapto 4,6-diamino pyrimidine and sodium hydroxide dissolved in a mixture of water and alcohol, the molar. amount of di-(beta-chloroethyl) ether P being approximately one-halfthat of the molar amount of 2-mercapto 4,6-diamino pyrimidine, heating the resulting mixture under reflux at the boiling temperature of the mass for a period of the order of 7 hours, filtering off the precipitate comprising beta,beta'-bis-(4,6-diamino pyrimidyl-2 thio) diethyl ether that separates upon cooling the mass, washing the said precipitate with water to remove soluble salts, and drying the Washed material.

GAETANO F. DALELIO. JAMES W. UNDERWOOD. 

